|Year : 2017 | Volume
| Issue : 1 | Page : 8-11
Spectrum of extrathyroidal congenital malformations in a cohort of North Indian children with permanent primary congenital hypothyroidism
Devi Dayal1, Rajendra Prasad2, Savita Bhunwal2, Rakesh Kumar2, Rohit Manoj Kumar3, Kushaljit Singh Sodhi4
1 Department of Pediatrics, Pediatric Endocrinology and Diabetes Unit, Advanced Pediatrics Center, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Cardiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||20-Feb-2017|
Department of Pediatrics, Pediatric Endocrinology and Diabetes Unit, Advanced Pediatrics Center, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Background: Children with permanent primary congenital hypothyroidism (CH) are at increased risk for extrathyroidal congenital malformations (ECMs) as compared to normal child population. A wide variation in the prevalence of ECMs in CH has been reported previously with the reports from Turkey and India indicating a much higher prevalence (48%–59%) as compared to reports from other countries (2.1%–10.5%). Setting and Design: Pediatric Endocrinology Clinic of a large multispecialty hospital located in Northwest India. Retrospective study. Materials and Methods: Children diagnosed as permanent primary CH underwent evaluation for associated ECMs using echocardiography and abdominal and pelvic ultrasonography if clinically indicated. Results: The etiological diagnoses in 106 children (52 girls and 54 boys) with permanent CH were thyroid agenesis in 70 (66%), ectopia in 9 (8.5%), hypoplasia in 6 (5.5%), hypothyroidism with eutopic gland in 5 (4.7%), and dyshormonogenesis in 16 (15%) patients. Seven (7.42%) patients had associated ECMs. The majority (4, 3.7%) of ECMs were cardiac (ventricular septal defect in two patients and patent ductus arteriosus and transposition of great arteries in one each), while skeletal (congenital talipes equinovarus in two and hemivertebra in one patient) and genitourinary (splitting of the pelvicalyceal system in two patients) anomalies were seen in 3 (2.8%) and 2 (1.8%) patients, respectively. Conclusion: The prevalence of ECMs in children with permanent CH was much lower as compared to other cohorts from India. Further studies are needed to determine the underlying genetic and environmental factors to explain the drastic regional differences in the prevalence of ECMs in CH.
Keywords: Children, congenital hypothyroidism, dyshormonogenesis, extrathyroidal congenital malformations, prevalence, thyroid dysgenesis
|How to cite this article:|
Dayal D, Prasad R, Bhunwal S, Kumar R, Kumar RM, Sodhi KS. Spectrum of extrathyroidal congenital malformations in a cohort of North Indian children with permanent primary congenital hypothyroidism. Thyroid Res Pract 2017;14:8-11
|How to cite this URL:|
Dayal D, Prasad R, Bhunwal S, Kumar R, Kumar RM, Sodhi KS. Spectrum of extrathyroidal congenital malformations in a cohort of North Indian children with permanent primary congenital hypothyroidism. Thyroid Res Pract [serial online] 2017 [cited 2018 Apr 20];14:8-11. Available from: http://www.thetrp.net/text.asp?2017/14/1/8/200559
| Introduction|| |
Congenital hypothyroidism (CH) is a common thyroid disorder in children with an estimated incidence of 1:3000–1:4000 live births. Children with CH are at increased risk for extrathyroidal congenital malformations (ECMs) in comparison with normal child population., The majority of the ECMs are cardiac, but malformations of other organ systems have also been reported.,, The spectrum of ECMs in these patients ranges from single to multiple defects.,, The prevalence of ECMs in patients with CH has been reported to vary in different patient populations. While majority of the reports indicate a low prevalence (although higher than the prevalence of congenital anomalies in normal children) of about 10%,,, data from Southern India suggest an unusually high prevalence of 59%. A recent study from Turkey has also reported a high (48%) prevalence of ECMs. In particular, the prevalence of cardiac ECMs was noted to be 22% and 29% in these two studies,, much higher than an average of about 5% in the previous reports., Unlike the previous studies from other countries which were conducted on large patient populations, the patient numbers in the studies showing a higher prevalence of ECMs were small. We have been following a large cohort of children with permanent CH at our hospital and thus aimed to determine the prevalence of ECMs in these patients.
| Materials and Methods|| |
A retrospective analysis of clinic data of children diagnosed as permanent primary CH and attending the Pediatric Endocrinology Clinic of our hospital between January 2011 and December 2015 was performed. Hypothyroidism was diagnosed in these patients on the basis of low serum total thyroxine and elevated serum thyroid stimulating hormone levels according to reference ranges. The ascertainment of etiological diagnosis was done by technetium- 99m pertechnetate thyroid scintigraphy and thyroid ultrasonography performed routinely in our hospital at the time of initial evaluation in all patients with CH. Perchlorate discharge test and antithyroid peroxidase antibodies were also performed for determining exact etiology as described previously. Children with subclinical hypothyroidism (SH), transient hypothyroidism (TH), syndromic diagnosis with known risk for associated congenital anomalies, autoimmune thyroid disease (AITD), and those with incomplete information in files were not included in the analysis. The search for ECMs was done in all patients by a thorough clinical examination, ultrasonography of abdomen and pelvis, and echocardiography. Ultrasonography for etiological diagnosis, as well as for detection of ECMs, was performed using ultrasound machine equipped with a 3–12 MHz high-frequency linear transducer, 3–8 MHz sector array, and 2–5 MHz convex array probes (Philips HD11XE, Philips Healthcare, DA Best, The Netherlands). Evaluation for structural heart disease was done by two-dimensional echocardiography (Siemens Acuson Sequoia C512, Siemens Medical Solutions, Boulevard, USA).
| Results|| |
During the study period, 186 children were registered in the clinic with a diagnosis of primary CH; only 106 (52 girls and 54 boys) were eligible for inclusion into the study. Reasons for exclusion were syndromic diagnoses in thirty patients, SH in 27, TH in 14, incomplete information in 8, and AITD in 1 patient. The most common, syndromic exclusion was Down syndrome (DS) in 28 patients; 20 of these had SH. The mean age of patients was 20.4 months (range: 0.25–204 months). The etiology of permanent CH was thyroid agenesis in 70 (66%), ectopia in 9 (8.5%), hypoplasia in 6 (5.5%), hypothyroidism with eutopic gland in 5 (4.7%), and DH in 16 (15%) patients. Associated ECMs were present in 7 (7.42%) patients. Cardiac malformations accounted for the majority (4, 3.7%) of ECMs followed by skeletal (3, 2.8%) and genitourinary (2, 1.8%) anomalies. Two patients had multiple anomalies. The cardiac ECMs included ventricular septal defect in two patients and patent ductus arteriosus and transposition of great arteries in one each. Skeletal ECMs were congenital talipes equinovarus in two patients and hemivertebra (D6) in one patient. Genitourinary anomalies were a mild splitting of the pelvicalyceal system in two patients. One patient had a cleft palate. Third-degree consanguinity was reported in two families of the cohort.
| Discussion|| |
The prevalence of ECMs in our patients with permanent primary CH was found to be much lower (7.42%) than previously reported (59%) from Southern India. The high prevalence (41%) of spina bifida occulta in the previous report probably contributed to an unusually high prevalence of ECMs. We however did not actively search for the presence of spinal dysraphism in our patients unless clinically indicated. The overall prevalence of ECMS in our patients was similar to most of the reports from the other countries.,,,,,
The usual prevalence of cardiac ECMs in patients with CH varies between 2.1% and 10.5%.,,,,, The Italian registry of CH recorded an increasing prevalence of cardiac ECMs from 2.1% to 5.5% over a decade., A prevalence of 6.25% was seen in an Iranian population of CH patients. In a Japanese study, cardiac ECMS were noted in 8.9% of a large cohort of children with CH. The Egyptian group recorded a prevalence of 9.09% in patients with CH due to TD. A high prevalence of 10.5% was observed by Kreisner et al. from Brazil. The results of our study are consistent with most of these previous reports. However, the prevalence of cardiac ECMs was lower in our study as compared to the previous reports from India , and Turkey. A large number of patients in the South Indian study had features of dysmorphism probably related to CH itself. However, the possibility of that some of these patients had distinct genetic syndromes which increase the risk of ECMs cannot be completely excluded. Similarly, majority of the patients in the study from Turkey also had dysmorphism suggestive of syndromic diagnoses. Genetic factors that account for the drastic differences in the prevalence of other diseases among North and South Indians could play an additional role for the reported differences in cardiac ECMs also. Another reason for a different prevalence of ECMs in our patient population could be related to the effects of consanguinity on the prevalence of genetic disorders in different populations. Although a decrease in the frequency of consanguineous marriages has been observed over the past few decades, the reported consanguinity rates are still much higher in Southern India as compared to the Northwestern India. Consanguinity increases the risk of defective genes being transmitted to the children from the parents and hence the prevalence of congenital malformations. A significant association has been observed between consanguinity and various genetic disorders, congenital heart disease, multiple congenital anomalies, neurological malformations, chromosomal disorders, and mental retardation. The higher prevalence of ECMs in the studies from Brazil and Turkey could also be due to the higher consanguinity rates in these populations.,
In the present study, the frequency of cardiac ECMs in children with CH was higher than the usual prevalence of about 2% in the normal population indicating an increased risk in CH. The higher risk is probably attributable to the genetic factors underlying the etiology of permanent CH. The presence of genetic component in permanent CH is indicated by its increased occurrence in patients with DS, familial component in TD, and its association with advanced maternal age  and hearing impairment. The higher frequency of ECMs in CH also indicates the presence of a genetic component in the etiology of CH. Although the molecular mechanisms underlying the developmental events of heart and thyroid are not fully elucidated, mutations in genes that control thyroid development are also associated with cardiac malformations., During embryonic life, development of thyroid gland is closely associated with the developing heart. It has been suggested that the molecular mechanisms that lead to problems in differentiation or migration of thyroid gland during embryonic life may also be involved in septation of the embryonic heart. Further research is needed to understand the genetic mechanisms underlying the embryonic development of thyroid and heart.
| Conclusion|| |
We report a lower prevalence of ECMs as compared to other Indian cohorts of children with permanent CH. This is the largest study from India exploring the presence of ECMs in permanent CH. Further research is needed to understand the genetic and environmental factors responsible for regional differences in the prevalence of ECMs in permanent CH.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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